Search

Longitudinal motion significantly contributes to the contraction of the ventricles. We studied the left (LV) and right ventricular (RV) longitudinal functions in 75 anthracycline-exposed, long-term childhood cancer survivors and 75 healthy controls with conventional echocardiography, tissue Doppler imaging (TDI), speckle tracking echocardiography (STE) of the mitral and tricuspid annular motion, and real-time three-dimensional echocardiography (RT-3DE). Cardiac magnetic resonance (CMR) imaging was performed on 61 of the survivors. The survivors had lower systolic myocardial velocities in the LV and lower diastolic velocities in both ventricles by TDI than did their healthy peers. The STE-based tissue motion annular displacement (TMAD) values describing the LV and RV systolic longitudinal function (MAD and TAD mid%, respectively) were also lower among the survivors (15.4 ± 2.4 vs. 16.1 ± 2.2 %, p = 0.049 and 22.5 ± 3.0 vs. 23.5 ± 3.0 %, p = 0.035). MAD and TAD mid in millimeters correlated with the respective ventricular volumes measured with RT-3DE or CMR.Childhood cancer survivors exposed to low to moderate anthracycline doses had decreased longitudinal systolic and diastolic functions (TDI or STE) compared with healthy controls. The STE-based TMAD is a fast and reproducible method to assess cardiac longitudinal function. What is Known? • High anthracycline doses cause LV dysfunction as evidenced by a decreased ejection fraction. What is new? • Low to moderate anthracycline doses also have a negative impact on the LV and RV longitudinal systolic and diastolic function. • TMAD is a new and fast method to assess the cardiac longitudinal function after anthracycline exposure.

Background 6-Mercaptopurine (6MP) and methotrexate (MTX) based maintenance therapy is a critical phase of childhood acute lymphoblastic leukemia treatment. Wide interindividual variations in drug disposition warrant frequent doses adjustments, but there is a lack of international consensus on dose adjustment guidelines. Procedure To identify relapse predictors, we collected 28,255 data sets on drug doses and blood counts (median: 47/patient) and analyzed erythrocyte (Ery) levels of cytotoxic 6MP/MTX metabolites in 9,182 blood samples (median: 14 samples/patient) from 532 children on MTX/6MP maintenance therapy targeted to a white blood cell count (WBC) of 1.5–3.5 × 109/l. Results After a median follow-up of 13.8 years for patients in remission, stepwise Cox regression analysis did not find age, average doses of 6MP and MTX, hemoglobin, absolute lymphocyte counts, thrombocyte counts, or Ery levels of 6-thioguanine nucleotides or MTX (including its polyglutamates) to be significant relapse predictors. The parameters significantly associated with risk of relapse (N = 83) were male sex (hazard ratio [HR] 2.0 [1.3–3.1], P = 0.003), WBC at diagnosis (HR = 1.04 per 10 × 109/l rise [1.00–1.09], P = 0.048), the absolute neutrophil count (ANC; HR = 1.7 per 109/l rise [1.3–2.4], P = 0.0007), and Ery thiopurine methyltransferase activity (HR = 2.7 per IU/ml rise [1.1–6.7], P = 0.03). WBC was significantly related to ANC (Spearman correlation coefficient, rs = 0.77; P

Timely and reliable detection of viruses is of key importance in early diagnosis of infection(s) following allogeneic HSCT. Among the immunocompetent, infections with BKPyV and JCPyV are mostly subclinical, while post-HSCT, the former may cause HC and the latter PML. The epidemiology and clinical impact of the newly identified KIPyV, WUPyV, MCPyV, and TSPyV in this context remain to be defined. To assess the incidence and clinical impact of BKPyV, JCPyV, KIPyV, WUPyV, MCPyV, and TSPyV infections, we performed longitudinal molecular surveillance for DNAemias of these HPyVs among 53 pediatric HSCT recipients. Surveillance pre-HSCT and for three months post-HSCT revealed BKPyV DNAemia in 20 (38%) patients. Our data demonstrate frequent BKPyV DNAemia among pediatric patients with HSCT and the confinement of clinical symptoms to high copy numbers alone. MCPyV and JCPyV viremias occurred at low and TSPyV viremia at very low prevalences. KIPyV or WUPyV viremias were not demonstrable in this group of immunocompromised patients.

When offered participation in clinical trials, families of children with cancer face a delicate balance between cure and toxicity. Since parents and children may perceive this balance differently, this paper explores whether adolescent patients have different enrollment patterns compared to younger children in trials with different toxicity profiles.

10536 Background: We previously developed a risk factor model in HR-NBL1/SIOPEN patients treated without DB including age, LDH and metastatic site index (MSI). We tested if this score (Morgenstern, PBC 2018) would provide meaningful information in DB treated HR-NBL1/SIOPEN patients. Methods: High-risk patients (stage 4 ≥1yr.; stage 4 < 1yr. with MYCN amplification (MNA); stage 2, 3, 0-21y with MNA) received intensive induction, surgery, high dose therapy (HDT) and local radiotherapy (21Gy). Patients with a ≤9 months intervall till HDT/SCT, ≥ partial response prior and no progression received up to 5 cycles of 100mg/m2 DB: as short-term (STI: 5 days) or long-term infusion (LTI: 10 days ) ± 6 (STI) or 3 (LTI) x 106 IU/m2 subcutaneous interleukin 2 (scIL2 over 2 x 5 days) followed by 2 weeks of 160mg/m2 oral isotretinoin. Results: DB was used in 1018 patients [512 males; 89% Stage, 1% Stage 4s, 10% loc. MNA; 2.8 yrs median age at diagnosis] in 18 countries. STI was used in 61% patients, LTI in 39% and DB without scIL2 in 62% patients. 2-yrs. event-free (EFS)/overall survival (OS) was 0.65±0.02/0.78±0.01 and 5-yrs. EFS/OS of 0.56±0.02/0.63±0.02. 891/1018 patients were evaluable for risk factor analysis. EFS multivariate analysis included age, MSI, LDH ≥1250U/L, HDT typ, response prior DB, DB schedule and use of scIL2: only age > 1.5yrs.(p = 0.002) and MSI > 1 (p = 0.002) had independent prognostic prediction. If restricted to stage 4 only, LDH ≥1250U/L was also an independent factor (p = 0.049). Points were allocated in proportion to the log-cumulative hazard ratio (cHR): cHR for LDH > 1250U/L was 1.33 (score of 1), cHR for age > 5 years and metastatic site involvement (MSI) > 1 were 1.79 and 1.86 (scores of 2). Using the score (0 to 5) relevant risk groups can be identified: 5-yrs. EFS/OS for scores 0&1 are 0.80±0.06&0.77±0.04, score 2/3 are 0.58±0.03&0.57±0.04 and for scores 4/5 are 0.50±0.06&0.43±0.08. Conclusions: The score adds value in DB treatment groups as it differentiates prognostic subgroups facilitating decision making for future DB add on treatments. Clinical trial information: NCT01704716.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Adults with acute lymphoblastic leukemia (ALL) do worse than children. From 7/2008 to 12/2014, Nordic and Baltic centers treated 1509 consecutive patients aged 1-45 years with Philadelphia chromosome-negative ALL according to the NOPHO ALL2008 without cranial irradiation. Overall, 1022 patients were of age 1-9 years (A), 266 were 10-17 years (B) and 221 were 18-45 years (C). Sixteen patients (three adults) died during induction. All others achieved remission after induction or 1-3 intensive blocks. Subsequently, 45 patients (12 adults) died, 122 patients relapsed (32 adults) with a median time to relapse of 1.6 years and 13 (no adult) developed a second malignancy. Median follow-up time was 4.6 years. Among the three age groups, older patients more often had higher risk ALL due to T-ALL (32%/25%/9%, P

Because of the rarity of neuroblastoma and poor survival until the 1990s, information on late effects in neuroblastoma survivors is sparse. We comprehensively reviewed the long-term risk for somatic disease in neuroblastoma survivors. We identified 721 5-year survivors of neuroblastoma in Nordic population-based cancer registries and identified late effects in national hospital registries covering the period 1977-2012. Detailed treatment information was available for 46% of the survivors. The disease-specific rates of hospitalization of survivors and of 152,231 randomly selected population comparisons were used to calculate standardized hospitalization rate ratios (SHRRs) and absolute excess risks (AERs). During 5,500 person-years of follow-up, 501 5-year survivors had a first hospital contact yielding a SHRR of 2.3 (95% CI 2.1-2.6) and a corresponding AER of 52 (95% CI 44-60) per 1,000 person-years. The highest relative risks were for diseases of blood and blood-forming organs (SHRR 3.8; 95% CI 2.7-5.4), endocrine diseases (3.6 [3.1-4.2]), circulatory system diseases (3.1 [2.5-3.8]), and diseases of the nervous system (3.0 [2.6-3.3]). Approximately 60% of the excess new hospitalizations of survivors were for diseases of the nervous system, urinary system, endocrine system, and bone and soft tissue. The relative risks and AERs were highest for the survivors most intensively treated. Survivors of neuroblastoma have a highly increased long-term risk for somatic late effects in all the main disease groups as compared to background levels. Our results are useful for counseling survivors and should contribute to improving health care planning in post-therapy clinics.

Background Asparaginase is an essential drug for childhood acute lymphoblastic leukemia (ALL) and is frequently given for months to obtain continuous asparagine depletion. This causes significant toxicity. We randomized patients to continuous versus intermittent asparaginase, hypothesizing decreased toxicity with unchanged efficacy (www.clinicaltrials.gov: NCT00819351). Methods Children (median age: 4·2 years) treated for non-high risk ALL according to the NOPHO ALL2008 protocol received five intramuscular pegylated asparaginase injections (1·000 IU/m2) biweekly and were then randomized to additional three (6 weeks intervals, N=309, experimental arm) versus ten (two weeks intervals, N=316, standard arm) doses. Primary endpoint was non-inferior (6% margin) disease free survival (DFS). Toxicity reduction was secondary endpoint. Occurrence of asparaginase-associated hypersensitivity, osteonecrosis, pancreatitis and thromboembolism were prospectively registered at quarterly intervals. Findings After a median follow-up of 4·1 years, the 7-year DFS was 90·4% (95% confidence interval, 85·4-95·4) and 90·8% (95% confidence interval, 87·0-94·6) in the experimental and standard arms, respectively. The 3-year cumulative incidence of any first toxicity (hypersensitivity (N=13), osteonecrosis (N=29), pancreatitis (N=24), thromboembolism (N=17)) was 9·3% in the experimental arm and 18·1% in the standard arm (P=0·001). Toxicity reduction was confirmed in sex- and risk group-adjusted Cox regression analysis stratified by age (≥10 and

Objectives This randomized controlled trial tested the hypothesis that children with non-high risk acute lymphoblastic leukemia could benefit from individualized 6-mercaptopurine increments during consolidation therapy (NCT00816049). Primary and secondary end points were end of consolidation minimal residual disease (MRD) positivity and event-free survival. Methods 392 patients were randomized to experimental and 396 to standard therapy. Patients allocated to standard therapy received oral 6-mercaptopurine (25 mg/m2/day) from days 30 to 85, while the experimental arm received stepwise increments of additional 25 mg/m2/day beginning on days 50 and/or 71 unless dose-limiting myelosuppression had occurred. Results In the experimental arm, 166 patients (42%) received one dose increment, and 62 (16%) received two. 57 of 387 (15%) in the experimental arm were MRD positive at end of consolidation versus 77 of 389 (20%) in the control arm (P=0.08). Five-year probability of event-free survival was 0.89 (95% CI: 0.85–0.93) in the experimental arm versus 0.93 (0.90–0.96) in the control arm (P=0.13). The median accumulated length of 6-mercaptopurine treatment interruptions was 7 (IQR 2–12) in the experimental arm versus 4 (IQR 0–10) in the control arm (P=0.002). Conclusion This study found no benefit from individualized 6-mercaptopurine increments compared to standard therapy. This article is protected by copyright. All rights reserved.

Graft-versus-host disease (GvHD) remains a major treatment-related risk in patients undergoing stem cell transplantation. Although advances in HLA-typing and graft types have reduced the risk of GvHD, a breakthrough in the treatment of severe GvHD is still lacking. Allogenic stem cell transplant has potentially beneficial immunological effects on the malignant disease necessitating transplantation, and the importance of these effects must be considered when treating GvHD.

Patients with Langerhans cell histiocytosis (LCH) refractory to conventional chemotherapy have a poor outcome. There are currently two promising treatment strategies for high-risk patients: the first involves the combination of 2-chlorodeoxyadenosine and cytarabine; the other approach is allogeneic haematopoietic stem cell transplantation (HSCT). Here we evaluated 87 patients with high-risk LCH who were transplanted between 1990 and 2013. Prior to the year 2000, most patients underwent HSCT following myeloablative conditioning (MAC): only 5 of 20 patients (25%) survived with a high rate (55%) of transplant-related mortality (TRM). After the year 2000 an increasing number of patients underwent HSCT with reduced intensity conditioning (RIC): 49/67 (73%) patients survived, however, the improved survival was not overtly achieved by the introduction of RIC regimens with similar 3-year probability of survival after MAC (77%) and RIC transplantation (71%). There was no significant difference in TRM by conditioning regimen intensity but relapse rates were higher after RIC compared to MAC regimens (28% vs. 8%, P = 0·02), although most patients relapsing after RIC transplantation could be salvaged with further chemotherapy. HSCT may be a curative approach in 3 out of 4 patients with high risk LCH refractory to chemotherapy: the optimal choice of HSCT conditioning remains uncertain.

Background The surgical treatment of Ewing's sarcoma family tumours (ESFTs) is challenging especially with axial tumours. The aim of the study was to analyse surgical treatment and outcome in a nationwide, population-based material consisting of surgically treated axial and peripheral ESFTs of bone and soft tissue. Methods The data were collected from the Finnish National Cancer Registry and the medical records of patients diagnosed during 1990–2009. Fifty-seven patients with surgically treated ESFTs were included, 22 with an axial and 35 with a peripheral primary tumours. The surgical treatment, its complications, survival and prognostic factors were analysed. Results Fifty-four patients underwent surgery with a curative intent and three underwent de-bulking operations. Bone reconstruction was performed in six patients with an axial and 15 with a peripheral tumour. Positive resection margins were associated with a worse five-year local relapse-free survival (33% vs. 84% for those with resection margins free of tumour cells, p = 0.003). The five-year sarcoma-specific survival was affected only by an axial location of the primary (61% vs. 89% for those with a peripheral tumour, p = 0.031). The late complications were mainly associated with bone reconstruction and more frequent among patients with a peripheral compared to an axial tumour (p = 0.031). Conclusions In the treatment of ESFTs, achieving adequate resection margins is crucial to avoid local relapses. Surgical complications are common particularly with bone reconstruction.

Aim The role that plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiac troponins T (cTnT) and I (cTnI) play in supplementing imaging to screen for cardiac late effects remains controversial and the impact of high-sensitivity cTnT and troponin-specific autoantibodies (cTnAAbs) remains unexplored. We studied the role of cardiac biomarkers as indicators of the late effects of anthracyclines among childhood cancer survivors. Methods We measured NT-proBNP, cTnT, high-sensitivity cTnT, cTnI and cTnAAbs in 76 childhood cancer survivors at a median of 9 years after primary diagnosis. The survivors underwent conventional and real-time three-dimensional echocardiography and 62 underwent cardiac magnetic resonance imaging (MRI). Results Of the survivors, four (5.3%) without risk factors for cardiotoxicity were cTnAAb-positive with an impaired cardiac function in MRI. Another four (5.3%) had an abnormal NT-proBNP level associated with an abnormal cardiac function and risk factors for cardiotoxicity. None showed measurable cardiac troponins, determined by the three different methods, with even the high-sensitivity cTnT-levels remaining normal. Conclusion Elevated plasma NT-proBNP or cTnAAbs indicated that childhood cancer survivors benefitted from being evaluated with modern imaging, despite normal function in conventional echocardiography. However, troponins did not seem to provide additional information on the late cardiotoxicity of anthracyclines.

Nowadays, allogeneic haematopoietic stem cell transplantation (allo-HSCT) is a well-established treatment procedure and often the only cure for many patients with malignant and non-malignant diseases. Decrease in short-term complications has substantially contributed to increased survival. Therefore long-term sequelae are reaching the focus of patient care. One of the most important risks of stem cell transplant survivors is infertility. As well as in the field of allo-HSCT also the field of reproductive medicine has achieved substantial advances to offer potential options for fertility preservation in both boys and girls. Access to these procedures as well as their financing differs significantly throughout Europe. As all European children and adolescents should have the same possibility, the Paediatric Diseases Working Party of the European Society for Blood and Marrow Transplantation organised an expert meeting in September 2015. This manuscript describes the recommendations for the diagnosis and pre-emptive procedures that should be offered to all children and adolescents in Europe who have to undergo an allo-HSCT.

Cord blood transplantation (CBT) from HLA-identical siblings is an attractive option for patients with bone marrow failure (BMF) syndrome because of the low risk of graft-versus-host disease (GVHD) and the absence of risk to the donor. We analyzed outcomes of 117 patients with inherited or acquired BMF syndrome who received CBT from a related HLA-identical donor in European Society for Blood and Marrow Transplantation centers between 1988 and 2014. Ninety-seven patients had inherited and 20 patients acquired BMF syndrome. Eighty-two patients received a single cord blood (CB) unit, whereas 35 patients received a combination of CB and bone marrow cells from the same donor. Median age at CBT was 6.7 years, and median follow-up was 86.7 months. The cumulative incidence function (CIF) of neutrophil recovery was 88.8% (95% CI, 83.1% to 94.9%), 100-day CIF of grades II to IV acute GVHD was 15.2%, and 7-year CIF of chronic GVHD was 14.5%. Overall survival at 7 years was 87.9% (95% CI, 80.8% to 92.6%), 89% for inherited and 81% for acquired BMF syndromes (P=.66). Results of this study are consistent with outcomes of bone marrow transplantation shown by previous series in the same setting and indicate that in pediatric patients with BMF syndrome, CBT from an HLA-identical sibling donor is associated with excellent long-term outcomes and that collection of CB unit at birth of a new sibling is strongly recommended. (C) 2017 American Society for Blood and Marrow Transplantation.

Background High-dose chemotherapy (HDC) with hematopoietic progenitor cell transplantation is a standard option for relapsed/refractory testicular germ-cell tumor (GCT), but only few data have been reported in female patients with GCT. We conducted a retrospective analysis of female patients with GCT treated with HDC and registered with the European Society for Blood and Marrow Transplantation. Patients and methods Between 1985 and 2013, 60 registered female patients with GCT, median age 27 years (range 15–48), were treated with salvage HDC. Forty patients (67%) had primary ovarian GCT, 8 (13%) mediastinal, 7 (12%) retroperitoneal and 5 (8%) other primary sites/unknown. Twenty-two patients (37%) received HDC as second-line therapy, 29 (48%) as third-line, and 9 (15%) as fourth- to sixth-line. Nine of 60 patients (15%) received HDC as late-intensification with no evidence of metastasis before HDC. The conditioning HDC regimens comprised carboplatin in 51 of 60 cases (85%), and consisted of a single HDC cycle in 31 cases (52%), a multi-cycle HDC regimen in 29 (48%). Results Nine cases who underwent late intensification HDC were not evaluable for response. Of the other 51 assessable patients, 17 (33%) achieved a complete response (CR), 8 (16%) a marker-negative partial remission (PRm−), 5 (10%) a marker-positive partial remission, 5 (10%) stable disease, and 13 (25%) progressive disease. There were 3 toxic deaths (6%). With an overall median follow-up of 14 months (range 1–219), 7 of 9 (78%) patients with late intensification and 18 of the 25 patients (72%) achieving a CR/PRm− following HDC were free of relapse/progression. In total, 25 of 60 patients (42%) were progression-free following HDC at a median follow-up of 87 months (range 3–219 months). Conclusions Salvage HDC based on carboplatin represents a therapeutic option for female patients with relapsed/refractory GCT.

Recurrent and clonal genetic alterations are characteristic of different subtypes of T- and B-cell lymphoblastic leukemia (ALL), and several subtypes are strong independent predictors of clinical outcome. A next-generation sequencing based multiplex ligation-dependent probe amplification variant (digitalMLPA) has been developed enabling simultaneous detection of copy number alterations (CNAs) of up to 1000 target sequences. This novel digitalMLPA assay was designed and optimized to detect CNAs of 56 key target genes and regions in ALL. A set of digital karyotyping probes has been included for the detection of gross ploidy changes, to determine the extent of CNAs, while also serving as reference probes for data normalization. Sixty-seven ALL patient samples (including B- and T-cell ALL), previously characterized for genetic aberrations by standard MLPA, array comparative genomic hybridization, and/or single-nucleotide polymorphism array, were analyzed single blinded using digitalMLPA. The digitalMLPA assay reliably identified whole chromosome losses and gains (including high hyperdiploidy), whole gene deletions or gains, intrachromosomal amplification of chromosome 21, fusion genes, and intragenic deletions, which were confirmed by other methods. Furthermore, subclonal alterations were reliably detected if present in at least 20% to 30% of neoplastic cells. The diagnostic sensitivity of the digitaLMLPA assay was 98.9%, and the specificity was 97.8%. These results merit further consideration of digitalMLPA as a valuable alternative for genetic work-up of newly diagnosed ALL patients.

Hepatotoxicity is a known toxicity to treatment of childhood acute lymphoblastic leukemia. Hepatotoxicity occurs during maintenance therapy and is caused by metabolites of 6-Mercaptopurine (6 MP) and Methotrexate (MTX). Our objective was to investigate the association between alanine aminotransferases (ALAT) levels and relapse rate. We included 385 patients enrolled in the NOPHO ALL-92 protocol. Data on ALAT levels, 6 MP and MTX doses, cytotoxic MTX/6 MP metabolites, and thiopurine methyltransferase (TPMT) activity were prospectively registered. In total, 91% of the patients had a mean ALAT (mALAT) level above upper normal limit (40 IU/L) and ALAT levels were positively correlated to 6 MP doses (rs=0.31; P

Viral infections remain the cause of key complications following haematopoietic stem cell transplantation (HSCT). The impact of multiple, concurrent viral reactivations/infections remains to be delineated.The clinical correlates of single or multiple viremic infections following HSCT and especially the occurrence of respiratory viruses in the bloodstream were investigated. We retrospectively searched for 23 viruses in a total of 184 sera from 53 paediatric patients. The time-points of interest were pre-HSCT, one, two and three months post-HSCT, and at discharge or death. The viruses were analyzed by quantitative or qualitative PCR.Of the 53 patients, 13 (25%) had viraemias by multiple viruses and 27 (51%) by a single virus. Thirteen patients (25%) had no viruses detected by PCR during the study period. In the children with viremic co-infections, polyomaviruses predominated over herpes viruses. Nearly half the patients, 24/53 (45%) had a polyomavirus in their serum at one or more time-points. At 12/15 time-points and in 11/13 patients with co-infections polyomaviruses were involved, compared with 6/15 time-points and 6/13 patients for cytomegalovirus. Acute graft-versus-host disease (GvHD) and steroid use were significant risk factors for the viraemias caused by more than one virus.Viral co-detection is a common finding in children undergoing HSCT. With large-scale viral screening also viruses other than CMV could be found as potential pathogens. In this study, BKPyV predominated over CMV as a contributor in viraemias caused by multiple viruses in children receiving HSCT.

Teema : lastenlääkkeet. English summary

HSCT is associated with a high risk of late morbidity. The aim of this study was to evaluate the frequency, time frame, risk factors, and possible etiology of pulmonary dysfunction following allogeneic HSCT in childhood. We evaluated the pulmonary function of 51 HSCT patients (>6 yr), by including FVC and FEV1 values prior to (baseline) and annually up to five yr after HSCT. A Cox proportional hazards model was used to analyze the risk factors for a pulmonary event. Over half (59%) of the patients developed pulmonary dysfunction, mainly consisting of restrictive abnormalities. Acute GvHD (HR 4.31, 95% CI 1.47-12.63), chronic GvHD (HR 10.20, 95% CI 2.42-43.03), and an abnormal baseline pulmonary function (HR 4.82, 95% CI 1.02-22.84) were associated with post-transplant dysfunction. FEV1 (p < 0.001) and FVC (p < 0.001) declined significantly by 12 months after HSCT and both remained below the pre-HSCT level at up to four yr post-transplantation. HSCT in childhood is associated with early and persistent restrictive impairment of pulmonary function. Patients with extensive chronic GvHD are particularly vulnerable to severe pulmonary dysfunction. Scheduled pulmonary function testing is warranted as part of the follow-up of survivors of HSCT in childhood.

Novel activating STAT5B mutations as putative drivers of T-cell acute lymphoblastic leukemia

The European Clinical Trials Directive of 2004 has increased the amount of paper work and reduced the number of initiated clinical trials. Particularly multinational trials have been delayed. To meet this challenge we developed a novel, simplified, fast and easy strategy for on-line toxicity registration for patients treated according to the Nordic/Baltic acute lymphoblastic leukaemia protocol, NOPHO ALL 2008, for children and young adults, including three randomisations. We used a risk-assessment based approach, avoiding reporting of expected adverse events and instead concentrating on 20 well-known serious, but rarer events with focus on changes in therapy introduced in the treatment protocol. This toxicity registration strategy was approved by the relevant regulatory authorities in all seven countries involved, as compliant within the EU directive of 2004. The centre compliance to registration was excellent with 98.9% of all patients being registered within 5 weeks from the requested quarterly registration. Currently, four toxicities (thrombosis, fungal infections, pancreatitis and allergic reactions) have been chosen for further detailed exploration due to the cumulative fraction of patients with positive registrations exceeding 5%. This toxicity registration offers real-time toxicity profiles of the total study cohort and provides early warnings of specific toxicities that require further investigation.

BACKGROUND: The improved survival rates for childhood acute lymphoblastic leukemia (ALL) may be jeopardized by the development of a second cancer, which has been associated with thiopurine therapy.PROCEDURE: We retrospectively analyzed three sequential Nordic Society of Paediatric Haematology and Oncology's protocols characterized by increasing intensity of thiopurine-based maintenance therapy. We explored the risk of second cancer in relation to protocols, risk group, thiopurine methyltransferase (TPMT) activity, ALL high hyperdiploidy (HeH), and t(12;21)[ETV6/RUNX1].RESULTS: After median 9.5 years (interquartile range, 5.4-15.3 yrs) of follow-up, 40 of 3,591 patients had developed a second cancer, of whom 38 had non-high-risk B-cell precursor ALL. Patients with standard-risk ALL, who received the longest maintenance therapy, had the highest adjusted hazard of second cancer (hazard ratio [HR], intermediate vs. standard risk: 0.16, 95% CI: 0.06-0.43, P < 0.001; HR, high vs. standard risk: 0.09, 95% CI: 0.02-0.49, P = 0.006); no significant effects of protocol, age, or white blood cell count at diagnosis, ALL HeH, or t(12;21)[ETV6/RUNX1] were observed. A subset analysis on the patients with standard-risk ALL did not show an increased hazard of second cancer from either HeH or t(12;21) (adjusted HR 2.02, 95% CI: 0.69-5.96, P = 0.20). The effect of low TPMT low activity was explored in patients reaching maintenance therapy in clinical remission (n = 3,368); no association with second cancer was observed (adjusted HR 1.43, 95% CI: 0.54-3.76, P = 0.47).CONCLUSIONS: The rate of second cancer was generally highest in patients with low-risk ALL, but we could not identify a subset at higher risk than others.

Background: PCR of rearranged antigen receptor genes is the method of choice for MRD quantification in ALL. Although FCM-MRD is faster and biologically more informative than PCR, the analysis requires a high level of training. The only larger published studies using FCM-MRD based stratification (Borowitz, Blood, 2008 and 2015) showed a clear association with clinical outcome in BCP-ALL. However, MRD analyses were centralized and these studies included only one MRD-based stratification (MRD levels at the end of induction). Patients and methods: We examined FCM-MRD as stratification tool in BCP-ALL at various timepoints in a large-scale multicenter (18 MRD centers) study. A total of 1487 patients with BCP-ALL (1298 children (younger than 18 years) and 189 adults (18-45 years) are included in the study and were treated according to the NOPHO ALL2008 protocol between July 2008 and February 2016. The median follow-up time for patients in first remission was 51 months (IQR 32-75). MRD was measured by FCM and/or real time quantitative PCR on days 15, 29 (end of induction) and 79 (for standard (SR) and intermediate risk (IR) patients) and prior to and after high risk blocks. A 6-colour FCM analysis including 3 standardized antibody combinations was used and performed in 18 laboratories. Patients were stratified by FCM-MRD, or by PCR-MRD if no FCM-MRD marker was available. End-of-induction MRD (cut-off 10-3) was used to stratify patients to standard risk (SR) vs intermediate risk (IR) or IR vs high risk consolidation therapy (in case of WBC > 100 x 109/L at diagnosis). Patients with MRD >=2.5x10-1 on day 15 were stratified to high risk block therapy. Patients with MRD >=5x10-2 on day 29 or day 79/post high risk-2 block MRD >=10-3 were stratified to HSCT. Primary outcomes were 5year event-free survival (5y EFS) and 5year cumulative incidence of relapse (5y CIR). Results: Only two patients (0.14% of total) had neither an informative FCM nor a PCR marker, and an informative FCM marker combination for MRD monitoring was identified in 96.2% of patients. There was a significant correlation between FCM- and PCR-MRD levels on day 15 (r=0.77, p Based on FCM-MRD only, the median MRD level on day 15, 29 and 79/post high risk-2 block was 5x10-3, 1.1x10-4, and below detection limit, respectively. Adults had significantly higher MRD levels at all time-points (p The day 29 FCM-MRD level was closely associated with clinical outcome and a higher hazard of relapse was seen independently for a FCM-MRD >=10-3 (hazard ratio (HR) 2.4, CI 1.6-3.7, p18 year (HR 3.0, CI 1.7-5.3, p=100 (HR 2.7, CI 1.6-4.6, p=0.0001), and B-other (HR 2.1, CI 1.2-3.5, p=0.0052) or high risk B-ALL cytogenetic aberration (rearranged KMT2A/iAMPchr21/hypodiploid) (HR 3.2, CI 1.6-6.1, p=0.0006) (multivariate cause-specific Cox regression, n=1328). Patients with a day 79 FCM-MRD >=10-4 and =10-4 and =10-4 and Patients with day 15 FCM-MRD =10-3 and Conclusion: FCM-MRD performed in a multi-center setting is a clinically useful method for disease monitoring and MRD-based treatment stratification in BCP-ALL. Moreover, FCM-MRD is a reliable indicator of outcome in BCP-ALL independently of other key risk factors. Residual disease >=10-4 and Disclosures No relevant conflicts of interest to declare.

Purpose: The population-based incidence of severe osteonecrosis (ON) necessitating total joint arthroplasty (TJA) in patients with hematological cancer is unknown. This study assessed the incidence of ON requiring primary TJA in children and young adults treated for leukemia or lymphoma. Methods: Patients diagnosed with leukemia or lymphoma before 31 years of age were identified from the Finnish and Danish Cancer Registries. These data were combined with those from the National Hospital Discharge and the Finnish Arthroplasty Registers. Data on the orthopedic procedures performed and the appropriate diagnosis codes given before the age of 40 were also retrieved. Results: The estimated cumulative incidence of TJA was 4.5% at 20 years for patients treated for chronic myeloid leukemia, followed by 2.1% for patients treated for acute myeloid leukemia. It was considerably lower in patients with acute lymphoblastic leukemia (ALL; 0.4%). Multivariate analysis revealed that allogeneic stem cell transplantation (allo-SCT) increased the risk of TJA (hazard ratio [HR]=9.4; 95% CI: 5.3-16.9). The risk of TJA was higher in patients diagnosed with cancer at 10-19 and 20-30 years of age than in those diagnosed before the age of 10 (HR=24; 95% CI: 3.1-176 and HR=26; 95% CI: 3.6-192 respectively). Conclusion: The incidence of ON requiring TJA was highest among patients with myeloid leukemias and lowest in patients treated for ALL. Allo-SCT and age ≥10 years at diagnosis were the most important risk factors for ON requiring TJA in hematological malignancies.

Relapse of childhood acute lymphoblastic leukemia (ALL) may reflect both inherent chemoresistance of the leukemic clone and adverse drug disposition that primarily is determined by genetic polymorphisms . In the current Nordic–Baltic ALL2008 protocol, as well as in many other contemporary ALL protocols, all post‐induction treatment phases include the thiopurines, 6‐thioguanine or 6‐mercaptopurine (6‐MP), and the latter constitutes, together with methotrexate (MTX), the backbone of maintenance therapy. 6MP has a relatively narrow therapeutic index, and because 6MP disposition varies substantially, standard dosing may lead to under treatment and relapse in some patients 2 and life‐threatening toxicity or second malignant neoplasia (SMN) in others . 6‐mercaptopurine is a prodrug and its cytotoxicity depends on conversion to 6‐thioguanine nucleotides (TGN). TGN are incorporated into DNA (DNA‐TG) and are occasionally mismatched to thymidine, causing cell death by post‐replicative mismatch repair . The enzyme thiopurine methyltransferase (TPMT) methylates 6MP and thereby reduces the amount of the drug available for TGN formation . However, the methylated metabolite methyl‐thioinosine monophosphate (Me‐TIMP) is a potent inhibitor of purine de novo synthesis, which enhances the incorporation of TGN into DNA . Nucleotide polymorphisms in the TPMT gene results in approximately 90% of Caucasians being homozygous for high TPMT activity (TPMTwild type), 10% carry one low activity allele (TPMT heterozygous) and 1 in 300 carries two low activity alleles (enzyme deficient) . 6MP/MTX maintenance therapy studies have showed far higher red blood cell TGN levels (Ery‐6TGN) and lower relapse rates in patients with low TPMT activity compared with wild‐ type patients . This is noteworthy, since patients are adjusted to the same target white blood cell count (WBC) during maintenance therapy, and TPMT low activity patients obtain only slightly lowerWBC levels than TPMT wild type (TPMT) patients during maintenance . Nevertheless, virtually nothing is known about how these two groups differ in DNA‐TG levels during 6MP based maintenance therapy. As part of Nordic/Baltic NOPHO ALL2008 pharmacology studies we here report preliminary data on the effect of low activity TPMT variants (TPMT) on the levels of the end‐point metabolite DNA‐TG and its relation to TPMT enzyme activity, Ery‐TGN, and erythrocyte levels of methylated metabolites (Ery‐ MeMP) in a cohort of children with ALL undergoing 6MP/MTX maintenance therapy.

Aim The birth prevalence of sacrococcygeal teratoma (SCT) has been reported to range from 1:27 000 to 1:40 000. We assessed the population-based prevalence and clinical presentation of SCT over 22 years. Methods We identified all cases of SCT, including live births, stillbirths and terminations of pregnancy (TOPs), in the Finnish Register of Congenital Malformations, covering 1987–2008. Data on prenatal diagnoses, pregnancy outcomes, infant deaths and associated anomalies were collected. Results One hundred and twenty four SCT cases were identified among 1 331 699 pregnancies. There were 89 (72%) live births, 13 (10%) stillbirths and 22 (18%) TOPs. The total prevalence of SCT was 1:10 700. Tumours were detected in utero in 55% of the pregnancies with SCT. The proportion of perinatal deaths among all SCT births was 28%. Thirty percentage of the cases had associated abnormalities (mainly of the urinary tract and various syndromes). Conclusion This nationwide, population-based study on SCT shows that the total and birth prevalence of SCT in Finland is markedly higher than previously reported. This may reflect true differences between populations, but may also be explained by accurate nationwide registration of SCTs. The high perinatal mortality rate has an impact on counselling of families and planning of deliveries.

Among the immunocompetent, infections with parvovirus B19 (B19V) and human bocavirus (HBoV) 1 range clinically from asymptomatic to severe, while following allogeneic hematopoietic SCT (HSCT) B19V can cause a persistent severe illness. The epidemiology and clinical impact of HBoV1 and the other emerging parvovirus 4 (PARV4) among immunocompromised patients have not been established. To determine the occurrence and clinical spectrum of B19V, PARV4 and HBoV1 infections, we performed a longitudinal molecular surveillance among 53 allogeneic HSCT recipients for pre- and post-HSCT DNAemias of these parvoviruses. Quantitative real-time PCR showed B19V DNA in sera of 16 (30%) patients, at mean levels of 4.6 × 10(3), 9.9 × 10(7), 1.1 × 10(10) and 1.6 × 10(2) B19V DNA copies/mL pre-HSCT (9/53), and at 1 (6/53), 2 (4/53) and 3 months (1/25) post HSCT, respectively. However, no clinical manifestation correlated with the presence of B19V viremia. All B19V sequences were of genotype 1. None of the sera investigated contained PARV4 or HBoV1 DNAs. Our data demonstrate B19V viremia to be frequent among pediatric allogeneic HSCT recipients, yet without apparent clinical correlates. PARV4 or HBoV1 viremias were not seen in these immunocompromised patients.

6-Mercaptopurine (6MP) and methotrexate (MTX) based maintenance therapy is a critical phase of childhood acute lymphoblastic leukemia treatment. Wide interindividual variations in drug disposition warrant frequent doses adjustments, but there is a lack of international consensus on dose adjustment guidelines.To identify relapse predictors, we collected 28,255 data sets on drug doses and blood counts (median: 47/patient) and analyzed erythrocyte (Ery) levels of cytotoxic 6MP/MTX metabolites in 9,182 blood samples (median: 14 samples/patient) from 532 children on MTX/6MP maintenance therapy targeted to a white blood cell count (WBC) of 1.5-3.5 × 10After a median follow-up of 13.8 years for patients in remission, stepwise Cox regression analysis did not find age, average doses of 6MP and MTX, hemoglobin, absolute lymphocyte counts, thrombocyte counts, or Ery levels of 6-thioguanine nucleotides or MTX (including its polyglutamates) to be significant relapse predictors. The parameters significantly associated with risk of relapse (N = 83) were male sex (hazard ratio [HR] 2.0 [1.3-3.1], P = 0.003), WBC at diagnosis (HR = 1.04 per 10 × 10This study indicates that a low neutrophil count is likely to be the best hematological target for dose adjustments of maintenance therapy.

Germ cell tumors (GCTs) comprise a heterogeneous group of tumors derived from primordial germ cells. The incidence of malignant testicular GCTs has increased in recent decades, but little is known about possible changes in malignant female GCTs. Population-based data covering all malignant GCTs in both sexes remain limited. All cases of malignant GCTs in 1969–2008 were collected from the Finnish Cancer Registry and their age-adjusted annual incidences calculated. The overall incidence of malignant GCTs was 2.56 per 100,000 person-years in males and 0.34 per 100,000 in females. The incidence of gonadal GCTs increased from 2.27 to 8.36 per 100,000 in males between 15 and 44 years of age. Moreover, the incidence of all histological subtypes of gonadal GCTs increased in males. In females, the only increase was seen in the incidence of ovarian non-dysgerminoma (from 0.07 to 0.29/100,000). The incidence of extragonadal GCTs did not change during the study period, being 0.18 and 0.10 per 100,000 in males and females, respectively. The incidence of gonadal GCTs in males increased significantly during the 40-year study period, whereas in females, no such change was observed. There were significant gender differences regarding the distribution of histological subtypes and patients’ ages. However, the incidence of extragonadal GCTs remained low in both sexes. The differences in the incidences of gonadal GCTs derived from the same population suggest that the risk factors of these malignancies differ between the two sexes.

Aims: Loss of specific immunity follows allogeneic haematopoietic stem cell transplantation (HSCT) in the majority of cases. Responses to (re)vaccinations can be used as indicators of a functional immunological recovery. Methods: Twenty-three paediatric recipients of HSCT were enrolled in a single centre setting and responses to scheduled immunizations analysed. Results: Immunity to vaccine-preventable diseases was impaired post HSCT, but (re)vaccinations induced protective responses in 59–100%, depending on the vaccine, regardless of prior graft-versus-host disease (GVHD) history. Conclusion: Despite the marked impact of moderate to severe chronic prior GVHD on both the qualitative and quantitative T-cell recovery post allogenic HSCT, most paediatric recipients of allogeneic stem cell grafts appear to attain protective antibody levels after immunization.

The purpose of this study was the appraisal of the clinical and functional consequences of germline mutations within the gene for the IL-2 inducible T-cell kinase, ITK. Among patients with Epstein-Barr virus-driven lymphoproliferative disorders (EBV-LPD), negative for mutations in SH2D1A and XIAP (n=46), we identified two patients with R29H or D500T,F501L,M503X mutations, respectively. Human wild-type (wt) ITK, but none of the mutants, was able to rescue defective calcium flux in murine Itk(-/-) T cells. Pulse-chase experiments showed that ITK mutations lead to varying reductions of protein half-life from 25 to 69% as compared with wt ITK (107 min). The pleckstrin homology domain of wt ITK binds most prominently to phosphatidylinositol monophosphates (PI(3)P, PI(4)P, PI(5)P) and to lesser extend to its double or triple phosphorylated derivates (PIP2, PIP3), interactions which were dramatically reduced in the patient with the ITK(R29H) mutant. ITK mutations are distributed over the entire protein and include missense, nonsense and indel mutations, reminiscent of the situation in its sister kinase in B cells, Bruton's tyrosine kinase.

Leukemic cells from 230 children with newly diagnosed B-cell precursor ALL were tested for in vitro drug resistance to a panel of anti-cancer drugs. Minimal residual disease (MRD) was measured by RQ-PCR. During follow-up, 24 relapses occurred in the 159 children with MRD

Williams syndrome (WS) is a relatively rare multisystem neurodevelopmental disorder caused by a hemizygous deletion of contiguous genes on chromosome 7q11.23. Although WS does not predispose carriers to cancers, alterations of chromosome 7 are common in several human neoplasms. We report here a patient with WS and two different cancers, Burkitt lymphoma and Ewing sarcoma. Array-CGH analysis of the patient blood revealed a constitutive 1.4 million base pair deletion at 7q11.23, compatible with WS diagnosis. Pediatr Blood Cancer 2014; 61:1877–1879. © 2014 Wiley Periodicals, Inc.

Purpose In a previous analysis of 326 children with Philadelphia chromosome (Ph) –positive acute lymphoblastic leukemia (ALL) treated between 1986 and 1996, hematopoietic stem-cell transplantation from HLA-matched related donors, but not from unrelated donors, offered a superior outcome than chemotherapy alone. To evaluate the impact of recent improvements in chemotherapy and transplantation, we performed a similar analysis on patients treated in the following decade. Patients and Methods We analyzed 610 patients with Ph-positive ALL treated between 1995 and 2005 without tyrosine kinase inhibitor therapy. The median follow-up duration was 6.3 years. Results Complete remission was achieved in 89% of patients. The 7-year event-free survival and overall survival rates were superior in the present cohort compared with the previous cohort (32.0% ± 2.0% v 25.0% ± 3.0, respectively, P = .007; and 44.9% ± 2.2% v 36.0% ± 3.0%, respectively, P = .017). Compared with chemotherapy alone, transplantation with matched related donors or unrelated donors in first remission (325 patients) showed an advantage with increasing follow-up, suggesting greater protection against late relapses (hazard ratio at 5 years, 0.37; P < .001). In the multivariate Cox regression analysis accounting for treatment (transplantation v no transplantation), age, leukocyte count, and early response had independent impact on treatment outcome. Conclusion Clinical outcome of children and adolescents with Ph-positive ALL has improved with advances in transplantation and chemotherapy. Transplantations with matched related donors and unrelated donors were equivalent and offered better disease control compared with chemotherapy alone. Age, leukocyte count, and early treatment response were independent prognostic indicators. The results of this study will serve as a historical reference to evaluate the therapeutic impact of tyrosine kinase inhibitors on the outcome of Ph-positive ALL.

The "Osteopetroses" are genetic diseases whose clinical picture is caused by a defect in bone resorption by osteoclasts. Three main forms can be distinguished on the basis of severity, age of onset and means of inheritance: the dominant benign, the intermediate and the recessive severe form. While several genes have been involved in the pathogenesis of the different types of osteopetroses, the CLCN7 gene has drawn the attention of many researchers, as mutations within this gene are associated with very different phenotypes. We report here the characterization of 25 unpublished patients which has resulted in the identification of 20 novel mutations, including 11 missense mutations, 6 causing premature termination, 1 small deletion and 2 putative splice site defects. Careful analysis of clinical and molecular data led us to several conclusions. First, intermediate osteopetrosis is not homogeneous, since it can comprise both severe dominant forms with an early onset and recessive ones without central nervous system involvement. Second, the appropriateness of haematopoietic stem cell transplantation in CLCN7-dependent ARO patients has to be carefully evaluated and exhaustive CNS examination is strongly suggested, as transplantation can almost completely cure the disease in situations where no primary neurological symptoms are present. Finally, the analysis of this largest cohort of CLCN7-dependent ARO patients together with some ADO II families allowed us to draw preliminary genotype-phenotype correlations suggesting that haploinsufficiency is not the mechanism causing ADO II. The availability of biochemical assays to characterize ClC-7 function will help to confirm this hypothesis.

Delayed immune reconstitution and the ensuing opportunistic infections among children following hematopoietic stem cell transplantation (HSCT) are associated with increased treatment-related morbidity and mortality (TRM). We retrospectively evaluated the impact of viral infections on the posttransplant recovery of pediatric recipients of stem cell grafts as a reflection of their posttransplant immunoreconstitution in a single institution setting. The case histories of 124 children (during 1/1999-9/2006) were reviewed for infectious episodes, and correlated with their respective clinical parameters. Patients with a high risk for CMV received prophylaxis, but failures in the prophylaxis were common (40%). 110/124 (89%) of these allogeneic patients had at least one viral reactivation/clinical infection posttransplant. In this group of pediatric patients chronic GVHD (P or = 2) viral infections. Our data indicate that viruses are common pathogens among pediatric recipients of allogeneic stem cell grafts. In this group of patients multiple viral infections early on seem to reflect an even more severe degree of immunological derangement in the recipient and identify a group of patients with an increased risk of chronic GVHD and secondary graft failure.

Deletion in chromosome 9p involving the CDKN2A locus (9p21.3) is known in many malignancies. To detect this deletion in adolescent ALL patients we used oligo array CGH and studied 54 patients aged 10–25 years. Deletion rate was 25/54 (46%), of these 19/25 (76%) were homozygous. Small deletions (

Background Interest has recently been paid to adolescents and young adults with acute lymphoblastic leukemia, particularly because all reports so far published indicate that these patients have a better outcome when treated with pediatric rather than adult therapeutic protocols. There are different biological subtypes of acute lymphoblastic leukemia with distinct features and prognoses; the distribution of these subtypes is not well known among adolescents. We, therefore, studied acute lymphoblastic leukemia in adolescents and young adults aged 10 to 25 years in Finland.Design and Methods This population-based study included 225 consecutive patients aged 10–25 years diagnosed with acute lymphoblastic leukemia during 1990–2004. One hundred and twenty-eight patients (10–16 years) were treated with pediatric Nordic (NOPHO) protocols, and 97 patients (17–25 years) with Finnish Leukemia Group National protocols. We characterized the biological subtypes, clinical features and outcome of these patients.Results For the whole cohort, the remission rate was 96%, 5-year event-free survival 62% and overall survival 72%.The 5-year event-free survival was 67% for the pediatric treatment group and 60% for the adult treatment group (p=n.s.). Patients with inferior outcome were those with a white bood cell count ≥ 100×109/L, the Philadelphia chromosome and MLL. Good prognostic features were TEL-AML1, hyperdiploidy, and pediatric intermediate risk stratification.Conclusions Unlike all previous studies, we found that the outcome of adolescents and young adults with acute lymphoblastic leukemia treated with pediatric or adult therapeutic protocols was comparable. The success of the adult acute lymphoblastic leukemia therapy emphasizes the benefit of central referral of patients to academic centers and adherence to research protocols. Key words: acute lymphoblastic leukemia, adolescents, survival, treatment outcome, young adults.

Myeloablative conditioning continues to be employed in hematopoietic stem cell transplantation among patients with pediatric transplant indications. Fractionated TBI (fTBI) remains, with its considerable anti-leukemic potential, the cornerstone of conditioning in the most common of pediatric indications, ALL in its first, second or subsequent remission despite its well-established long-term sequelae. The feasibility of chemotherapy-only regimens has been established and these regimens widely employed in other pediatric indications, for example, in ALL below the age of 2 years, AML, myelodysplasias or severe aplastic anemia. Conditioning regimens are being modified with data accumulating on the role of, for example, pre-transplant residual disease, advanced HLA-typing or haploidentical transplantations in the pediatric setting.

Incompatibility in killer-cell immunoglobulin-like receptor (KIR) ligand between recipient and donor of hematopoietic stem cell transplantation has been reported to lead to natural killer (NK) cell activation. This activation may result in better transplantation outcome through reduced risk of graft-versus-host (GvH) disease, relapse and mortality. In the present study the effect of KIR ligand incompatibility was investigated retrospectively in 186 unrelated stem cell transplantations performed in Finland during years 1993–2004. No clear evidence for a better outcome in cases with KIR ligand incompatibility was obtained. Transplantation-related mortality was 64% in Kaplan–Meier analysis in the GvH direction KIR ligand-mismatched group and 33% in the KIR ligand-matched group. This difference was statistically non-significant. Consequently, no support could be obtained for a beneficial effect of KIR ligand incompatibility in the present set of unrelated donor transplantations.

Background Recent data indicate a role for angiogenesis in hematologic malignancies. In addition to promoting new vessel growth in the bone marrow microenvironment, angiogenic factors are regulators of both hematopoietic and leukemic cells. Activation of vascular endothelial growth factor receptor 3 (VEGFR-3) and Tie1 tyrosine kinase receptor are known to promote leukemia cell survival. The details of this complex angiogenesis-related interaction are still uncertain. Procedure We studied bone marrow samples from 73 patients with acute lymphoblastic (ALL) or myelogenous (AML) leukemia by using immunological methods. Results Vascular endothelial growth factor receptor 3 expression was found in 15% of the samples, particularly in samples with pediatric lymphoblastic leukemias and monocytic AMLs. Tie1 protein expression was found in 11% of the samples, all of which were from adult AML patients. Conclusions Our findings suggest that there are angiogenesis-related differences between pediatric and adult lymphoblastic leukemias as well as between lymphoid and myeloid leukemias. Pediatr Blood Cancer © 2006 Wiley-Liss, Inc.

Delayed and/or insufficient T cell recovery post hematopoietic stem cell transplantation (HSCT) leads to an increased risk of morbidity and mortality. We evaluated thymic function and its association with T cell regeneration post HSCT and identified factors involved in the process among pediatric stem cell transplant recipients. T cell regeneration in 66 pediatric patients was prospectively followed by naive T cell phenotyping, measuring of T cell receptor excision circles (TRECs) and expression of Foxp3 by regulatory T cells for the first 18 months post HSCT. TRECs were lower pre-HSCT in children with a malignant than non-malignant primary disease or immunosuppressed controls (P=0.001). Naive T lymphocyte reconstitution and thymic recovery were slow in the recipients of allogeneic stem cell grafts post HSCT. Infections caused by herpesviruses had a prognostic impact on mortality. Children with low TRECs had a high mortality (P=0.05) and low TRECs were also associated with extensive chronic graft-versus-host disease from 6 months onwards. Low amount of Foxp3 pre-HSCT was associated with an increased mortality post HSCT (P=0.03). Our study indicates an association between impaired T cell regeneration and thymic dysfunction and the clinical post transplant complications in pediatric allogeneic stem cell transplantation.

BACKGROUND This cross-sectional study evaluated the overall bone health and the prevalence of vertebral complications after stem cell transplantation (SCT) in prepubertal children and adolescents. METHODS A total of 44 children and adolescents (median age, 10 years) were evaluated at a median of 3.8 years after SCT for areal bone mineral density (aBMD) with dual-energy X-ray absoptiometry and for vertebral fractures with instant vertebral assessment. Pretransplant and posttransplant medications and nutritional parameters were recorded, and plasma levels of vitamin D, calcium, phosphate, and parathormone were measured. RESULTS Of the 44 patients, 16 (36%) had a BMD Z-score of

When offered participation in clinical trials, families of children with cancer face a delicate balance between cure and toxicity. Since parents and children may perceive this balance differently, this paper explores whether adolescent patients have different enrollment patterns compared to younger children in trials with different toxicity profiles.Age-dependent participation rates in three consecutive, randomized childhood leukemia trials conducted by the Nordic Society of Paediatric Haematology and Oncology were evaluated. The ALL2000 dexamethasone/vincristine (Dx/VCR) trial tested treatment intensifications to improve cure, and the back-to-back ALL2008 6-mercaptopurine (6MP) and ALL2008 PEG-asparaginase (ASP) trials tested treatment intensifications (6MP) and toxicity reduction without compromising survival (ASP). Patient randomization and toxicity data were prospectively registered by the treating physicians.Parents of young children favored treatment intensifications (Dx/VCR: 12% refusal; 6MP: 14%; ASP: 21%), whereas parents of adolescents favored treatment reductions (Dx/VCR: 52% refusal; 6MP: 30%; ASP: 8%). Adolescents were more likely to refuse intensification trials than young children (adjusted ORs 6.3; P0.01 [Dx/VCR] and 2.1; P = 0.04 [6MP]). Adolescents were less likely to refuse the ASP trial, with varying effect size depending on the length of the preceding consolidation treatment (adjusted OR for median consolidation length 0.15; P = 0.01). Younger children participated more frequently in only 6MP than in only ASP (14% vs. 5%), and adolescents vice versa (2% vs. 17%; P = 0.001).Parents' and adolescents' divergent inclinations toward intensified or reduced therapy emphasize the necessity of actively involving adolescents in the informed consent process, which should also address motives for trial participation.

Objectives Cure rates improve when adolescents and young adults with acute lymphoblastic leukemia (ALL) are treated according to pediatric protocols. Assumed risks of toxicities and associated delays in treatment have played a role in setting upper age limits. The aim of this study was to examine the toxicity profile and treatment delays in NOPHO ALL2008 comparing children and adults. Methods We collected information on 19 treatment-related toxicities, systematically captured at 3-month intervals throughout therapy, and time intervals between 12 consecutive treatment phases for 1076 patients aged 1–45 yrs treated according to the Nordic/Baltic ALL2008 protocol. Results No adults died during induction. The duration of induction therapy and postinduction treatment phases did not differ between children and adults, except for patients 18–45 yrs being significantly delayed during two of nine high-risk blocks (median number of days for patients 1–9, 10–17, and 18–45 yrs; the glucocorticosteroid/antimetabolite-based block B1: 24, 26, and 29 d, respectively, P = 0.001, and Block 5 (in most cases also a B block): 29, 29, and 37 d, respectively, P = 0.02). A higher incidence of thrombosis with increasing age was found; highest odds ratio 5.4 (95% CI: (2.6;11.0)) for patients 15–17 yrs compared with children 1–9 yrs (P